Depressive symptoms as risk factor or prodrome of dementia: multi-state cognitive transitions modified by age and polygenic risk - 20/04/26

Doi : 10.1016/j.tjpad.2026.100577

Ziyang Ren ^1,^2,^{^{#
Ziyang Ren and Ruyi Zhang contributed equally to this work.}}, Ruyi Zhang ^3,^4,^{^{#
Ziyang Ren and Ruyi Zhang contributed equally to this work.}}, Shuai Guo ³, Yihao Zhao ³, Jufen Liu ^1,^2,^5,^⁎ , Xiaoying Zheng ^3,^6,^⁎

¹ Institute of Reproductive and Child Health/National Health Commission Key Laboratory of Reproductive Health, School of Public Health, Peking University, No. 38 College Rd, Haidian District, Beijing 100191, PR China

² Department of Epidemiology and Biostatistics, School of Public Health, Peking University, No. 38 College Rd, Haidian District, Beijing 100191, PR China

³ School of Population Medicine and Public Health, Chinese Academy of Medical Science & Peking Union Medical College, No. 9 Dongdan Santiao, Dongcheng District, Beijing 100730, PR China

⁴ Beijing Ditan Hospital, Capital Medical University, No. 8 Jingshun East Street, Chaoyang District, Beijing, 100015, PR China

⁵ State Key Laboratory of Female Fertility Promotion, Peking University, No. 38 College Rd, Haidian District, Beijing 100191, PR China

⁶ Peking University, No.5 Yiheyuan Road, Haidian District, Beijing, P.R. China

^⁎ Correspondence: Jufen Liu, Institute of Reproductive and Child Health/National Health Commission Key Laboratory of Reproductive Health; Department of Epidemiology and Biostatistics, School of Public Health; State Key Laboratory of Female Fertility Promotion, Peking University, No. 38 College Rd, Haidian District, Beijing 100191, China, Phone number: +86-010-82801760-221 Institute of Reproductive and Child Health/National Health Commission Key Laboratory of Reproductive Health Department of Epidemiology and Biostatistics School of Public Health State Key Laboratory of Female Fertility Promotion Peking University No. 38 College Rd, Haidian District Beijing 100191 China ^⁎⁎ Xiaoying Zheng, School of Population Medicine and Public Health, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 31, Beijige-3, Dongsheng District, Beijing, 100730, China; Peking University, No.5 Yiheyuan Road, Haidian District, Beijing, P.R. China, Phone number: +86-010-65120036 School of Population Medicine and Public Health Chinese Academy of Medical Sciences & Peking Union Medical College Peking University No. 31, Beijige-3, Dongsheng District Beijing 100730 China

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ABSTRACT

Background

Whether depressive symptoms signal a risk factor or a prodromal symptom of dementia, and how this depends on age, genetic susceptibility, and cognitive stages, remains controversial.

Objectives

To examine the association between depressive symptoms and incident dementia and cognitive transitions, and to test effect modification by age and AD genetic susceptibility (APOE and AD polygenic risk score [PRS]).

Design

Longitudinal cohort study (1998-2020) using repeated assessments; incident dementia was modeled using Fine-Gray competing-risk models, and cognitive transitions were modeled with multi-state Markov models.

Setting

The U.S. Health and Retirement Study.

Participants

For the main incident dementia analysis, 13,225 dementia-free participants were included at baseline; genetic and repeated-measures analyses were restricted to 12,089 participants with complete PRS/APOE data.

Measurements

Depressive symptoms were assessed with the 8-item CES-D. Cognitive status was classified as normal cognition, subjective memory complaint (SMC), cognitive impairment no dementia (CIND), or dementia. AD genetic susceptibility was indexed by APOE and AD PRS. Outcomes included incident dementia and transitions across cognitive states.

Results

Baseline depressive symptoms (prevalence 11.3%) were associated with a higher incidence of dementia (sHR 1.24, 95% CI 1.10-1.39), with stronger associations in late midlife (50-59y: sHR 1.65) than ≥60y (sHR 1.19; P for interaction=0.001). After excluding dementia occurring within 5-10y, the associations for late midlife (but not ≥60y) remained significant (sHR for 5y=1.57; for 10y=1.55, both P for interaction≤0.030). AD PRS modified this association: depressive symptoms predicted dementia only among individuals with lower AD PRS, whereas APOE ε4 showed no modification. Multi-state analyses showed depressive symptoms accelerated progression across the cognitive continuum (e.g., normal cognition → SMC, HR=1.49; SMC → CIND, HR=1.33; CIND → dementia, HR=1.17) and reduced reversion to normal cognition. Furthermore, AD genetic susceptibility was positively associated with depressive symptom burden, specifically at the SMC stage.

Conclusions

Depressive symptoms in late midlife, especially with lower AD PRS, are more consistent with a potentially modifiable risk marker for dementia, whereas depressive symptoms emerging at SMC in genetically susceptible adults may more often reflect prodromal disease activity.

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Keywords : depressive symptoms, dementia, subjective memory complaint, polygenic risk score, multi-state model